A method and apparatus are disclosed for the confinement or containment of a catalyst either in an asymmetric membrane or in a composite membrane structure, which is subsequently used to conduct a chemical or biochemical reaction in which multiple phases (e.g. organic and aqueous) are involved.
"Immobilization" on solid-phase supports of otherwise homogeneous catalysts (including, but not limited to enzymes, whole cells, and non-biological catalysts such as various metal-containing coordination compounds) is useful because immobilization simplifies the separation of reaction products from catalyst and it facilitates the recovery and reuse of catalyst, which frequently is too expensive for one-time use. However, as discussed below, such catalyst immobilization is often accomplished by covalently attaching the catalyst to the support, generally via irreversible, covalent linking chemistry. As a result, when a supported catalyst becomes deactivated, as biocatalysts such as enzymes inevitably do, it is difficult if not impossible to replace the catalyst without at the same time replacing the support matrix. Replacement of the catalyst/support combination can be a considerably more expensive proposition than replacement of the catalyst component alone because of the cost of the immobilization chemistry and of the support itself.
Typical supports are membrane structures and particulate media such as microporous and gel-type beads. Membrane supports are attractive because membrane reactors have a number of performance advantages relative to packed-bed reactors employing catalysts bound to particulate support media. However, they have the significant disadvantage that membrane supports are expensive relative to particulate media. Accordingly, the costs associated with periodically replacing membrane-supported catalysts can be significantly higher than is the case with particulate supports.
A significant improvement in membrane bioreactor economics would result from the localization of catalysts in a membrane structure in such a way as to (1) provide effective containment of the catalyst in the membrane, (2) permit high effective catalyst loadings to be realized, and (3) make possible simple catalyst replacement by avoiding the covalent attachment of catalyst to the membrane surface. Such a technology would significantly reduce the cost of catalyst replacement in membrane reactors. Additionally, it could have secondary benefits of avoiding the use of immobilization chemistries that can be expensive and difficult to control and that sometimes can result in disappointing yields and/or activities of immobilized catalyst.
Many approaches exist for the immobilization of enzymes and homogeneous catalysts on solid supports. Several techniques including covalent bonding, crosslinking, entrapment, adsorption, and microencapsulation have been developed to render many enzymes water-insoluble. See FIG. 1A. Reviews of enzyme immobilization procedures have been published. Zaborsky, O. R., Immobilized Enzymes, CRC Press, Cleveland, Ohio (1973); Weetal, H. H., ed., Immobilized Enzymes, Antigens, Antibodies, and Peptides: Enzymology, Vol. 1, Marcel Dekker, N.Y. (1975); Gutcho, S. J., Immobilized Enzymes--Preparation and Engineering Techniques, Noyes Data Corp., Park Ridge, N.H. (1974). Several industrial processes currently employ immobilized enzymes or immobilized whole cells. Mosbach, K., "Application of Immobilized Enzymes," pp. 717-858 in Immobilized Enzymes, K. Mosbach, ed., Methods in Enzymology XLIV. Academic Press, N.Y. (1976).
The possibility of immobilizing non-biological, ionic homogeneous catalysts as the counterions in ion exchange resins has been recognized for over thirty years. Helfferich, F., Ion Exchange, McGraw-Hill, N.Y. (1971). More recently, homogeneous catalyst complexes have been tied to polymeric and ceramic supports via bifunctional ligands which are simultaneously coordinated with the active metal center and anchored to the solid support. Pittman, C. U., and Evans, G. O. Chemtech, 3, 560 (1975); Michalska, Z. M., and Webster, D. E., Chemtech, 5, 117 (1975); Grubbs, R. H., Chemtech, 7, 512 (1977); Bailar, J. C., Jr., Cat. Rev.--Sci. Eng., 10(1), 17 (1974). Examples are shown in FIGS. 1B and 1C.
Enzymes have been immobilized in membranes (as opposed to particles) in several different fashions. They have been covalently bound or crosslinked within porous membranes (Thomas, D., "Artificial enzyme membranes: transport, memory, and oscillatory phenomena," pp. 115-150 in Analysis and Control of Immobilized Enzyme Systems, D. Thomas and J. P. Kernevez, eds., American Elsevier, N.Y. (1976); Thomas, D., and Caplan, S. R., "Enzyme Membranes," pp. 351-398 in Membrane Separation Processes, P. Meares, ed., Elsevier, Amsterdam (1976); Fernandes, P. M., Constanides, A., Vieth, W. R., and Vendatasubramanian, K., Chemtech, 5, 438 (1975); Goldman, R., Kedem, O., and Katchalski, E., Biochem, 7, 4518 (1968)), attached to membrane surfaces (Emery, A., Sorenson, J., Kolarik, M., Swanson, S., and Lim, H., Biotechnol. Bioeng., 16, 1359 (1974)), entrapped in membrane gels (Blaedel, W. J., Kissel, T. R., and Bogulaski, R. C. Anal. Chem., 44, 2030 (1972); Blaedel, W. J., and Kissel, T. R., Anal. Chem., 47, 1602 (1975)), encapsulated by polymeric or liquid surfactant membrane microcapsules, (Chang, T. M. S., Artificial Cells, Charles C. Thomas, Springfield, Ill. (1972); Chang, T. M. S., and Kuntarian, N., pp. 193-197 in Enzyme Engineering 4, G. B. Brown, G. Manecke, and L. B. Wingard, eds., Plenum Press, N.Y. (1978); May, S. W., and Landgraff, L. M., Biochem. Biophys. Res. Commun., 68,786 (1976); Mohan, R. R., and Li, N. N., Biotechnol. Bioeng., 16, 513 (1974).) and confined to reaction vessels by ultrafiltration membranes (Porter, M. C., "Applications of Membranes to Enzyme Isolation and Purification," pp. 115-144 in Enzyme Engineering 3, L. B. Wingard, ed., Interscience, N.Y. (1972); Closset, G. P., Cobb, J. T., and Shah, Y. T., Biotechnol. Bioeng., 16, 345 (1974); Madgavkar, A. M., Shah, Y. T., and Cobb, J. T., Biotechnol. Bioeng., 19, 1719 (1977)). The latter type of containment with membranes has been called "figurative immobilization" by Weetal (Messing, R. A., ed., Immobilized Enzymes for Industrial Reactors, Academic Press, N.Y. (1975)), a term which also applies to the localization of an enzyme solution by hollow fibers (Rony, P. R., J. Am. Chem. Soc., 94, 8247 (1972); Davis, J. C., Biotechnol. Bioeng., 16, 1113 (1974); Lewis, W., and Middleman, S., AIChE J., 20, 1012 (1974); Waterland, L. R., Robertson, C. R., and Michaels, A. S., Chem. Eng. Commun., 2, 37 (1975)). Enzyme entrapment outside the fiber (i.e., within the "shell"), within the porous matrix, and in the fiber lumen have all been demonstrated in fully aqueous systems where reactants and products have been supplied and withdrawn, respectively, in aqueous process streams (see FIGS. 2A, 2B, 2C).
Every conceivable membrane geometry--planar films (Kay, T., Lilly, M. D., Sharp, A. K., and Wilson, R. J. H., Nature, 217, 641 (1968); Wilson, R. J. H., Kay, G., and Lilly, M. D., Biochem. J., 108, 845 (1968a); Wilson, R. J. H., Kay, G., and Lilly, M. D., Biochem. J., 109,137 (1968b)) and spiral-wrapped membranes (Vieth, W. R., Wang, S. S., Bernath, F. R., and Mogensen, A. O., "Enzyme Polymer Membrane Systems," pp. 175-202 in Recent Developments in Separation Science, Vol. 1, N. N. Li, ed., CRC Press, Cleveland, Ohio (1972); Broun, G., Thomas, D., Gellf, G., Domurado, D., Berjonneau, A. M., and Buillon, C., Biotechnol. Bioeng., 15, 359 (1973); Gautheron, D. C., and Coulet, P. R., pp. 123-127 in Enzyme Engineering 4, G. B. Broun, G. Manecke, and L. B. Wingard, eds., Plenum Press, N.Y. (1978)), tubular membranes, (Madgavkar, A. M. Shah, Y. T., and Cobb, J. T., Biotechnol. Bioeng., 19, 1719 (1977); Tachauer, E., Cobb, J. T., and Shah, Y. T., Biotechnol. Bioeng., 16, 545 (1974)) and hollow fibers and microcapsules--and nearly all membrane types--porous and nonporous, electrically charged and neutral--have been considered in connection with enzyme immobilization.